A novel class of compounds of the general formula (I), which act to antagonize the action of the glucagon hormone on the glucagon receptor. Owing to their antagonizing effect of the glucagon receptor the compounds may be suitable for the treatment and/or prevention of any diseases and disorders, wherein a glucagon antagonistic action is beneficial, such as hyperglycemia, Type 1 diabetes, Type 2 diabetes, disorders of the lipid metabolism and obesity. (I) wherein R2 is hydrogen or C1-6-alkyl, B is (II) Z is arylene or a divalent radical derived from a 5 or 6 membered heteroaromatic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur.

A compound of the general formula (I) : wherein R2 is hydrogen or C16alkyl, B is R38 is hydrogen, S (=O) 2C16alkyl orC (=O)C16alkyl, A is a valence bond, (CR3R4), or (CR3R4) (CR5R6), R', R3, R4, R5 and R6 independently are hydrogen or C16alkyl, Z is arylene or a divalent radical derived from a 5 or 6 membered heteroaromatic ring con taining 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, which may optionally be substituted with one or two groups R7 and R8 selected from halogen, CN, CF3, OCF3, NO2, OR9, NR9R10 and C16alkyl, wherein R9 and Rio independently are hydrogen or C16alkyl, X is wherein ris0 or1, q and s independently are 0,1, 2 or 3, R11, R12, R13 and R14 independently are hydrogen or C16alkyl, D is wherein R15, R16, R17 and R18 independently are hydrogen, halogen,CN,CH2CN,CHF2,CF3,OCF3,OCHF2,OCH2CF3,OCF2CHF2, S(O)2CF3, SCF3, NO2, OR21, NR21R22, SR21, NR21S(O)2R22, S(O)2NR21R22, S(O)NR21R22, S(O)R21, S(O)2R21, C(O)NR21R22, OC(O)NR21R22, NR21C(O)R22, CH2C (O) NR2'R22,OCH2C (O) NR2'R22,CH2OR2',CH2NR21R22,OC (O) R21C (O) R21 or C (O) OR<BR> <BR> C16alkyl, C26alkenyl or C26alkynyl, which may optionally be substituted with one or more substituents selected from halogen, CN, CF3, OCF3, NO2, OR21, NR21R22 and C16alkyl, C38cycloalkyl, C48cycloalkenyl, heterocyclyl, C38cycloalkylC16alkyl, C38cyclo alkylC, 6alkoxy, C38cycloalkyloxy, C38cycloalkylC16alkylthio, C38cycloalkylthio, C38cycloalkylC26alkenyl, C38cycloalkylC26alkynyl, C48cycloalkenylC16alkyl, C48cyclo alkenylC26alkenyl, C48cycloalkenylC26alkynyl, heterocyclylC16alkyl, heterocyclyl C26alkenyl, heterocyclylC26alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, arylC16alkoxy, arylC16alkyl, arylC26alkenyl, arylC26alkynyl, heteroaryl, heteroarylC16alkyl, heteroaryl C26alkenyl or heteroarylC26alkynyl, of which the cyclic moieties optionally may be substituted with one or more substituents se lected from halogen,CN,CF3,OCF3,NO2,oR2',NR2'R22 and Cl6alkyl, wherein R2'and R22 independently are hydrogen, C, 6alkyl or aryl, or R2'and R22 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R15 to R18 when placed in adjacent positions together may form a bridge (cR23R24) O(CR25R26)cO, wherein a is 0, 1 or 2, c is 1 or 2, R23, R24, R25 and R26 independently are hydrogen, C16alkyl or fluorine, R'9 and R20 independently are hydrogen, C16alkyl, C38cycloalkyl or C3cyclo alkylC16alkyl, E is wherein R27and R23 independently are hydrogen, halogen,CN,CF3,OCF3,oR32,NR32R33, C14alkyl, C38cycloalkyl, C48cyclo alkenyl or aryl, wherein the aryl group optionally may be substituted with one or more substituents selected from halogen, CN, CF3, OCF3, NO2, OR32, NR32R33 and C16alkyl, wherein R32 and R33 independently are hydrogen or Cl6alkyl, or R32 and R33 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocydic ring optionally containing one or two further het eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, R29, R30 and R31 independently are hydrogen, halogen,CHF2,CF3,OCF3,OCHF2,OCH2CF3,OCF2CHF2,SCF3,OR NR34R35, SR34, S(O)R34, S(O)2R34, C(O)NR34R35, OC(O)NR34R35, NR34C(O)R35, OCH2C(O)NR34R35, C(O0R34 or C(O)OR34, C16alkyl, C26alkenyl or C26alkynyl, which may optionally be substituted with one or more substituents selected from halogen, CN, CF3, OCF3, NO2, OR34, NR34R35 and C16alkyl, C38cycloalkyl, C48cycloalkenyl, heterocyclyl, C38cycloalkylC16alkyl, C3cyclo alkylC26alkenyl, C38cycloalkylC26alkynyl, C48cycloalkenylC16alkyl, C48cycloalkenyl C26alkenyl, C48cycloalkenylC26alkynyl, heterocyclylC16alkyl, heterocyclylC26alkenyl, heterocyclylC26alkynyl, aryl, aryloxy, aroyl, arylC16alkoxy, arylC16alkyl, arylC26alkenyl, arylC26alkynyl, heteroaryl, heteroarylC16alkyl, heteroarylC26alkenyl or heteroarylC26 alkynyl, of which the cyclic moieties optionally may be substituted with one or more substituents se lected from halogen,CN,CF3,OCF3,NO2,oR34,NR34R35 and C16alkyl, wherein R34 and R35 independently are hydrogen, C16alkyl or aryl, or R34 and R35 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R29, R30 and R31 when attached to the same ring carbon atom or differ <BR> <BR> <BR> ent ring carbon atoms together may form a radical O(CH2)tCR36R37(CH2)@O,<BR> <BR> <BR> <BR> <BR> <BR> (CH2)tCR36R37(CH2)@ or S(CH2)tCR36R37(CH2)@S, wherein t and I independently are 0,1, 2,3, 4 or 5, R36 and R37 independently are hydrogen or C16alkyl, as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutical acceptable salt thereof.

2.

A compound according to claim 1, wherein B is wherein A and R'are as defined in claim 1.

3.

A compound according to claim 1, wherein B is.

4.

A compound according to claim 1, wherein B is.

5.

A compound according to claim 1, wherein B is wherein W3 is as defined in claim 1.

6.

A compound according to claim 1 or 2, wherein R'is hydrogen.

7.

A compound according to any one of the claims 1,2 or 6, wherein A is a valence bond, CH2orCH2CH2.

8.

A compound according to claim 7, wherein A isCH2.

9.

A compound according to any one of the preceding claims, wherein R2 is hydrogen.

10.

A compound according to any one of the preceding claims, wherein Z is wherein R7 and R3 are as defined in claim 1.

11.

A compound according to claim 10, wherein Z is.

12.

A compound according to any one of the preceding claims, wherein X is wherein q is 0 or 1, r is 0 or 1, s is 0, 1 or 2, and R12 and R13 independently are hydrogen or C1 6alkyl.

A compound according to any one of the preceding claims, wherein D is wherein R15, R16, R17, R18, R19 and R20 are as defined in claim 1.

17.

A compound according to claim 16, wherein D is wherein R'5, R16 and R"are as defined in claim 1.

18.

A compound according to claim 16 or 17, wherein R15, R16 and R17 independently are hydrogen, halogen, CN, NO2, CF3, OCF3, SCF3, C16alkyl, C16alkoxy, SC16alkyl, C(O) OR21, C(O)R21, CH2OR21, C(O)NR21R22, S(O02R21, S(O)2CF3, S(O02NR21R22, C38cycloalkyl or aryl, or two of the groups R15, R16 and R17 when placed in adjacent posi tions together form a bridge (CR23R24)aO(CR25R26)cO, wherein R21 and R22 independently are hydrogen or C16alkyl, and a, c, R23, R24, R25 and R26 are as defined in claim 1.

19.

A compound according to claim 18, wherein R15, R'6 and R17 independently are hydro gen,SC16alkyl, halogen,CN,CF3,OCF3 or C16alkoxy, or wherein two of the substituents in adjacent positions form the bridge CF2OCF2O.

20.

A compound according to claim 19, wherein Rlr', Rt6 and R17 independently are hydro gen, halogen,SCH3,CF3 orOCF3, or wherein two of the substituents in adjacent positions form the bridge CF2OCF2O.

21.

A compound according to any one of the preceding claims, wherein E is wherein R27, R23, R29, R30 and Rare as defined in claim 1.

22.

A compound according to claim 21, wherein E is wherein R27 and R28 are as defined in claim 1. 23.

23.

A compound according to claim 21 or 22, wherein R 27 and e independently are hydro gen, C16alkyl, C38cycloalkyl, C48cycloalkenyl or phenyl.

24.

A compound according to claim 23, wherein R27 is hydrogen and R23 is C16alkyl, C48cycloalkenyl or C38cycloalkyl.

25.

A compound according to claim 21, wherein E is wherein R29, R30 and R31 are as defined in claim 1.

26.

A compound according to claim 25, wherein E is wherein R29, R30 and R31 are as defined in claim 1.

27.

A compound according to claim 25 or 26, wherein R29, R30 and R31 independently are hydrogen, CHF2, CF3, OCF3, OCHF2, OCH2CF3, OCF2CHF2, SCF3, OR34, NR34R35, SR34, S(O)R34, S(O)2R34, C(O)NR34R35, OC(O)NR34R35, NR34C(O)R35, OCH2C(O)NR34R35, C(O)R34 orC (O) OR34, # C16alkyl, C26alkenyl or C26alkynyl, which may optionally be substituted with one or more substituents selected from halogen, CN, CF3, OCF3, NO2, OR34, NR34R35 and C16alkyl, # C38cycloalkyl or C48cycloalkenyl, which may optionally be substituted with one or more substituents selected from halogen,CN,CF3,OCF3,NO2,oR34,NR34R35 and C16alkyl wherein R34 and R35 independently are hydrogen, C16alkyl or aryl, or R34 and R35 when attached to the same nitrogen atom together with the said nitro gen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.

28.

A compound according to claim 27, wherein R29, R30 and R31 independently are # hydrogen, C16alkoxy, CF3, OCF3 or NR34R35, wherein R34and R 35are as defined in claim 1, or C16alkyl, C3$cycloalkyl or C48cycloalkenyl, which are optionally substituted as de fined in claim 1.

29.

A compound according to claim 28, wherein R29, R30 and R31 independently are hydrogen or 'Ci. C38cycloalkyl or C48cycloalkenyl, which are optionally substituted as de fined in claim 1.

30.

A compound according to claim 29, wherein R29, R30 and R31 independently are hydro gen, C16alkyl, C38cycloalkyl or C48cycloalkenyl.

31.

A compound according to claim 30, wherein R29 and R31 are both hydrogen and R30 is C16alkyl, C38cycloalkyl or C48cycloalkenyl.

32.

A compound according to claim 31, wherein R29 and R31 are both hydrogen and R30 is C,6alkyl.

33.

A compound according to claim 1 of the general formula (la) : wherein R', R2, R3, R4, R7, R8, X, D and E are as defined in claim 1 or in any one of the pre ceding claims.

34.

A compound according to claim 33, wherein R1, R2, R3, R4, R7 and R8 are hydrogen.

35.

A compound according to claim 1 of the general formula (lb) : wherein R2, R7, R8, X, D and E are as defined in claim 1 or in any one of the preceding claims.

36.

A compound according to claim 1 of the general formula (lc) : wherein R2, R7, R8, X, D and E are as defined in claim 1 or in any one of the preceding claims.

37.

A compound according to claim 1 of the general formula (Id) : wherein R2, R, R8, R38, X, D and E are as defined in claim 1 or in any one of the preceding claims.

38.

A compound according to any one of claims 35 to 37, wherein R2, R7 and R8 are hydro gen.

39.

A compound according to any one of the preceding claims 1 to 20 or 33 to 38, wherein E is.

A compound according to any one of the preceding claims, which has an IC50 value of no greater than 5 iM as determined by the Glucagon Binding Assay (I) or Glucagon Binding As say (II) disclosed herein.

45.

A compound according to claim 44, which has an IC50 value of less than 1 MM, preferably of less than 500 nM and even more preferred of less than 100 nM as determined by the Glu cagon Binding Assay (I) or Glucagon Binding Assay (II) disclosed herein.

46.

A compound according to any one of the preceding claims, which is an agent useful for the treatment and/or prevention of an indication selected from the group consisting of hyper glycemia, IGT, Type 2 diabetes, Type 1 diabetes and obesity.

47.

A compound according to any one of the claims 1 to 46 for use as a medicament.

48.

A pharmaceutical composition comprising, as an active ingredient, at least one com pound according to any one of the claims 1 to 46 together with one or more pharmaceutically acceptable carriers or excipients.

49.

A pharmaceutical composition according to claim 48 in unit dosage form, comprising from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and espe cially preferred from about 0.5 mg to about 200 mg of the compound according to any one of the claims 1 to 46.

50.

Use of a compound according to any one of the claims 1 to 46 for the preparation of a medicament for the treatment and/or prevention of disorders or diseases, wherein a gluca gon antagonistic action is beneficial.

51.

Use of a compound according to any one of the claims 1 to 46 for the preparation of a medicament for the treatment and/or prevention of glucagonmediated disorders and dis eases.

52.

Use of a compound according to any one of the claims 1 to 46 for the preparation of a medicament for the treatment and/or prevention of hyperglycemia.

53.

Use of a compound according to any one of the claims 1 to 46 for the preparation of a medicament for lowering blood glucose in a mammal.

54.

Use of a compound according to any one of the claims 1 to 46 for the preparation of a medicament for the treatment and/or prevention of IGT.

55.

Use of a compound according to any one of the claims 1 to 46 for the preparation of a medicament for the treatment and/or prevention of Type 2 diabetes.

56.

Use according to claim 55 for the preparation of a medicament for the delaying or pre vention of the progression from IGT to Type 2 diabetes.

57.

Use according to claim 55 for the preparation of a medicament for the delaying or pre vention of the progression from noninsulin requiring Type 2 diabetes to insulin requiring Type 2 diabetes.

58.

Use of a compound according to any one of the claims 1 to 46 for the preparation of a medicament for the treatment and/or prevention of Type 1 diabetes.

59.

Use of a compound according to any one of the claims 1 to 46 for the preparation of a medicament for the treatment and/or prevention of obesity.

60.

Use according to any one of the claims 50 to 61 in a regimen which comprises treatment with a further antidiabetic agent.

61.

Use according to any one of the claims 50 to 61 in a regimen which comprises treatment with a further antiobesity agent.

62.

Use according to any one of the claims 50 to 61 in a regimen which additionally com prises treatment with an antihypertensive agent.

63.

A method for the treatment and/or prevention of disorders or diseases, wherein a gluca gon antagonistic action is beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of the claims 1 to 46 or a pharmaceutical composition according to claim 48 or 49.

64.

The method according to claim 63, wherein the effective amount of the compound is in the range of from about 0.05 mg to about 2000 mg, preferably from about 0.1 mg to about 1000 mg and especially preferred from about 0.5 mg to about 500 mg per day.

Description:

GLUCAGON ANTAGONISTSIINVERSE AGONISTS FIELD OF THE INVENTION The present invention relates to agents that act to antagonize the action of the glucagon peptide hormone on the glucagon receptor. More particularly, it relates to glucagon antagonists or inverse agonists.

BACKGROUND OF THE INVENTION Glucagon is a key hormonal agent that, in co-operation with insulin, medi- ates homeostatic regulation of the amount of glucose in the blood. Glucagon primar- ily acts by stimulating certain cells (mostly liver cells) to release glucose when blood glucose levels fall. The action of glucagon is opposite to that of insulin, which stimu- lates cells to take up and store glucose whenever blood glucose levels rise. Both glu- cagon and insulin are peptide hormones.

Glucagon is produced in the alpha islet cells of the pancreas and insulin in the beta islet cells. Diabetes mellitus is a common disorder of glucose metabolism.

The disease is characterized by hyperglycemia and may be classified as Type 1 dia- betes, the insulin-dependent form, or Type 2 diabetes, which is non-insulin- dependent in character. Subjects with Type 1 diabetes are hyperglycemic and hy- poinsulinemic, and the conventional treatment for this form of the disease is to pro- vide insulin. However, in some patients with Type 1 or Type 2 diabetes, absolute or relative elevated glucagon levels have been shown to contribute to the hyperglyce- mic state. Both in healthy control animals as well as in animal models of Type 1 and Type 2 diabetes, removal of circulating glucagon with selective and specific antibod- ies has resulted in reduction of the glycemic level (Brand et al., Diabetologia 37,985 (1994); Diabetes 43, [suppl 11, 172A (1994); Am. J. Physio. 269, E469-E477 (1995); Diabetes 44 [supp (1], 134A (1995) ; Diabetes 45,1076 (1996) ). These studies sug- gest that glucagon suppression or an action that antagonizes glucagon could be a useful adjunct to conventional treatment of hyperglycemia in diabetic patients. The action of glucagon can be suppressed by providing an antagonist or an inverse ago- nist, ie substances that inhibit or prevent glucagon-induced responses. The antago- nist can be peptidic or non-peptidic in nature.

Glucagon exerts its action by binding to and activating its receptor, which is part of the Glucagon-Secretin branch of the 7-transmembrane G-protein coupled re- ceptor family (Jelinek et al., Science 259,1614, (1993) ). The receptor functions by activating the adenylyl cyclase second messenger system and the result is an in- crease in cAMP levels.

The term"C24-alkynyl"as used herein represents a branched or straight hy- drocarbon group having from 2 to 6 carbon atoms and at least one triple bond. Ex- amples of such groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1- hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 2, 4-hexadiynyl and the like. : The term"C-alkoxy"as used herein refers to the radical-O-C1-alkyl, wherein C1-alkyl is as defined above. Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, terf-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.

The term"C3-cycloalkyl"as used herein represents a saturated, carbocyclic group having from 3 to 8 carbon atoms. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

The term"C4-8-cycloalkenyl"as used herein represents a non-aromatic, car- bocyclic group having from 4 to 8 carbon atoms containing one or two double bonds.

The term"heterocyclyl"as used herein represents a non-aromatic 3 to 10 membered ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur and optionally containing one or two double bonds. Representative examples are pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, tetrahy- drofuranyl and the like.

The term"aryl"as used herein is intended to include carbocyclic, aromatic ring systems such as 6 membered monocyclic and 9 to 14 membered bi-and tri- cyclic, carbocyclic, aromatic ring systems. Representative examples are phenyl, bi- phenylyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, azulenyl and the like. Aryl is also intended to include the partially hydrogenated derivatives of the ring systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1,2, 3, 4-tetrahydronaphthyl, 1, 4-dihydronaphthyl and the like.

"Aryl-C1-6-alkyl", "heteroaryl-C1-6-alkyl", "aryl-C2-6-alkenyl" etc. mean CI-6-alkyl or C24-alkenyl as defined above, substituted by an aryl or heteroaryl as defined above, for example : The term"optionally substituted"as used herein means that the groups in question are either unsubstituted or substituted with one or more of the substituents specified. When the groups in question are substituted with more than one substituent the substituents may be the same or different.

Certain of the above defined terms may occur more than once in the structural formulae, and upon such occurrence each term shall be defined independently of the other.

Furthermore, when using the terms"independently are"and"independently selected from"it should be understood that the groups in question may be the same or different.

DESCRIPTION OF THE INVENTION The present invention is based on the unexpected observation that the com- pounds of the general formula (I) disclosed below show a high binding affinity for the glucagon receptor and antagonize the action of glucagon.

Accordingly, the invention is concerned with compounds of the general for- mula (I) :

wherein R2 is hydrogen or C1-6-alkyl, Bis R38 is hydrogen, -S (=O) 2-C1-6-alkyl or-C (=O)-C1-6-alkyl, A is a valence bond, -(CR3R4)-, or -(CR3R4)(CR5R6)-, R1, R3, R4, R5 and R6 independently are hydrogen or C1-6-alkyl, Z is arylene or a divalent radical derived from a 5 or 6 membered heteroaromatic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, which may optionally be substituted with one or two groups R7 and R8 selected from halgoen, -CN, -CF3, -OCF3, -NO2, -OR9, -NR9R10 and C1-6-alkyl, wherein R9 and R10 independently are hydrogen or C1-6-alkyl, X is

wherein r is 0 or 1, q and s independently are 0,1, 2 or 3, R", R12, R13 and R14 independently are hydrogen or C1-6-alkyl, D is

C4-8-cycloalkenyl-C2-6-alkenyl, C4-8cycloalkenyl-C2-6-alkynyl, heterocyclyl-C1-6-alkyl, heterocyclyl-C2-6-alkenyl, heterocyclyl-C2-6-alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C1-6-alkoxy, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl or heteroaryl-C26-alkynyl, of which the cyclic moieties optionally may be substituted with one or more substitu- ents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR21, -NR21R22 and C1-6-alkyl, wherein R21 and R22 independently are hydrogen, C1-6-alkyl or aryl, or R21 and R22 when attached to the same nitrogen atom together with the said nitro- gen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R15 to R18 when placed in adjacent positions together may form a bridge -(CR23R24)a-O-(CR25R26)c-O-, wherein a is 0, 1 or 2, c is 1 or 2, R23, R24, R25 and R26 independently are hydrogen, C1-6-alkyl or fluorine, R'9 and R20 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl or C38-cyclo- alkyl-Cl-6-alkyl, Eis

wherein R27and R28 independently are hydrogen, halogen,-CN,-CF3,-OCF3,-OR32,-NR32W3, C1-6-alkyl, C3-8-cycloalkyl, C4. 8-cycloalkenyl or aryl, wherein the aryl group optionally may be substituted with one or more substituents selected from halogen,-CN,-CF3,-OCF3,-NO2,-oR32,-NR32R33 and C1-6-alkyl, wherein R32 and R33 independently are hydrogen or C1-6-alkyl, or R32 and R33 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally con- taining one or two double bonds, R29, R30 and R31 independently are hydrogen, halogen, -CHF2, -CF3,. -OCF3,. -OCHF2, -OCH2CF3, -OCF3CHF2, -SCF3, -OR34, -NR34R35, -SR34, -S(O)R34, -S(O)2R34, -C(O)NR34R35, -OC(O)NR34R35, -NR34C(O)R35, -OCH2C(O)NR34R35, -C(O)R34 or-C (O) OR34,

C16-alkyl, C26-alkenyl or C26-alkynyl, which may optionally be substituted with one or more substituents selected from <BR> <BR> halogen,-CN,-CF3,-OCF3,-N02,-OR34,-NR34R35 and C_6-alkyl,<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> C38-cycloalkyl, C48-cycloalkenyl, heterocyclyl, C38-cycloalkyl-C16-alkyl, C38-cyclo- alkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cyclo- alkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, heterocyclyl-C1-6-alkyl, heterocy- clyl-C26-alkenyl, heterocyclyl-C24-alkynyl, aryl, aryloxy, aroyl, aryl-C14-alkoxy, aryl- C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, hetero- aryl-C26-alkenyl or heteroaryl-C2-6-alkynyl, of which the cyclic moieties optionally may be substituted with one or more substitu- ents selected from halogen,-CN,-CF3,-OCF3,-NO2,-oR34,-NR34R35 and C16-alkyl, wherein R34 and R35 independently are hydrogen, C1-6-alkyl or aryl, or R34 and R35 when attached to the same nitrogen atom together with the said nitro- gen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R29, R30 and R31 when attached to the same ring carbon atom or different ring carbon atoms together may form a radical -O-(CH2)t-CR36R37-(CH2)l-O-, -(CH2)t-CR36R37-(CH2)l- or -S-(CH2)t-CR36R37-(CH2)l-S-, wherein t and I independently are 0,1, 2,3, 4 or 5, R36 and R37 independently are hydrogen or C1-6-alkyl, as well as any optical or geometric isomer or tautomeric form thereof including mix- tures of these or a pharmaceutically acceptable salt thereof.

In one embodiment B is

wherein A and R'are as defined for formula (I).

In a further embodiment A is a valence bond,-CH2-or-CH2CH2-, such as A-CH2-.

In ; still a further embodiment R'is hydrogen.

In another embodiment B is

In still another embodiment B is In yet another embodiment B is

wherein R38 is as defined for formula (I).

In still a further embodiment R2 is hydrogen.

In another embodiment Z is

wherein R7 and R8 are as defined for formula (I).

In still another embodiment Z is

wherein q is 0 or 1, r is 0 or 1, s is 0,1 or 2, and R12 and R13 independently are hy- drogen or C1-6-alkyl.

In another embodiment thereof R15, R16 and R17 and independently hydrogen, -S- C16-alkyl, halogen,-CN,-CF3,-OCF3 or C1-6-alkoxy, or wherein two of the substituents in adjacent positions form the bridge -CF2-O-CF2-O-.

In yet another embodiment thereof R'5, R16 and R17 are independently hydrogen, halogen,-S-CH3,-CF3 or-OCF3, or wherein two of the substituents in adjacent posi- tions form the bridge -CF2-O-CF2-O-.

In a further embodiment E is

wherein R", R", R29 R30 and R31 are as defined for formula (I).

In still a further embodiment E is

wherein R27 and R28 are as defined for formula (I).

In an embodiment thereof R27 and R28 are independently hydrogen, C-6-alkyl, C3-8-cycloalkyl, C4-8-cycloalkenyl or phenyl.

In another embodiment thereof R27 is hydrogen and R28 is C1-6-alkyl, C4-8-cycloalkenyl or C3-8-cycloalkyl.

In still another embodiment E is

wherein R29, R30 and R31 are as defined for formula (I).

In yet another embodiment E is wherein R29, R30 and R31 are as defined for formula (I).

In an embodiment thereof R29, R30 and R31 ae independently hydrogen,-CHFz,-CF3,-OCF3,-OCHF2,-OCH2CF3,-OCF2CHF2,-SCF3, -OR34, -NR34R35, -SR34, -S(O)R34, -S(O)2R34, -C(O)NR34R35, -OC(O)NR34R35, -NR34C(O)R35, -OCH2C(O)NR34R35, -C(O)R34 or -C(O)OR34, # C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl, which may optionally be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR34, -NR34R35 and C1-6-alkyl, # C38-cycloalkyl or C4-8-cycloalkenyl, which may optionally be substituted with one or more substituents selected from halgoen, -CN, -CF3, -OCF3, -NO2,. -OR34, -NR34R35 and C1-6-alkyl, wherein R34 and R35 independently are hydrogen, C16-alkyl or aryl,

or R34 and R35 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.

In another embodiment thereof R29, R30 and R3'are independently # hydrogen, C1-6-alkoxy, -CF3, -OCF3 or -NR34R35, wherein R34 and R35 are as defined for formula (I), or C1-6-alkyl, C3-8-cycloalkyl or C"-cycloalkenyl, which are optionally substituted as defined for formula (I).

In yet another embodiment thereof R29, R30 and R31 are independently hydrogen or # C1-6-alkyl, C3-8-cycloalkyl or C4-8-cycloalkenyl, which are optionally substituted as defined for formula (I).

In still another embodiment thereof R29 and R31 are both hydrogen and R3° is C1-6-alkyl, C3-8-cycloalkyl or C4-8-cycloalkenyl, such as C1-6-alkyl.

In another embodiment the invention relates to compounds of the general formula (la) :

wherein R', R2, R3, R4, R7, R8, X, D and E are as defined for formula (I) or as defined in the embodiments above.

In one embodiment thereof R', R2, R3, R4, R7 and R8 are hydrogen.

In another embodiment the invention relates to compounds of the general formula (lb): wherein R2, R7, R8, X, D and E are as defined for formula (I) or as defined in the em- bodiments above.

In still another embodiment the invention relates to compounds of the general for- mula (Ic) : wherein R2, R7, R8, X, D and E are as defined for formula (I) or as defined in the em- bodiments above.

In yet another embodiment the invention relates to compounds of the general formula (ld):

wherein R2, R7, R8, R38, X, D and E are as defined for formula (I) or as defined in the embodiments above.

In an embodiment R2, R7 and R8 are hydrogen in the formulae (la), (lb), (lc) and (ld).

In another embodiment E is In an embodiment of the formula (ld) X is-C (O) NHCH (CH3)- and E is In a further embodiment of formula (Id)-X-D is In still a further embodiment the invention relates to compound which is selected from 3-[1(R)-(4-bromophenyl)ethyl]-1-(4-tert-butylcyclohexyl)-1-{
4-[1-(R)-hydroxy-2-(2H- tetrazol-5-yl) ethyl] benzyl} urea,

3- [1 (R)- (4-chlorophenyl) ethyl]-1- (4-cyclohex-1-enylphenyl)-1- {4- [1- (R)-hydroxy-2- (2H- tetrazol-5-yl) ethyl] benzyl} urea, as well as any diastereomer or enantiomer or tautomeric form thereof including mix- tures of these or a pharmaceutical acceptable salt thereof.

In another aspect, the invention is concerned with compounds of the general formula (I') : wherein R2 is hydrogen or C1-6-alkyl, B is wherein A is a valence bond,-(CR3R4)-, or-(CR3R4) (CR5R6)-, R', R3, R4, R5 and R6 independently are hydrogen or C16-alkyl, Z is arylene or a divalent radical derived from a 5 or 6 membered heteroaromatic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, which may optionally be substituted with one or two groups R7 and R3 selected from halogen, -CN, -CF3, -OCF3,-NO2, -OR9, -NR9R10 and C1-6-alkyl,

wherein R9 and R10 independently are hydrogen or C1-6-alkyl, X is wherein ris0 or1, q and s independently are 0,1, 2 or 3, R", R12, R13 and R14 independently are hydrogen or C1-6-alkyl, D is

C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, heterocyclyl-C1-6-alkyl, heterocyclyl-C2-6-alkenyl, heterocyclyl-C2-6-alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C. 6-alkoxy, aryl-C16-alkyl, aryl-C26-alkenyl, aryl-C26-alkynyl, heteroaryl, heteroaryl-C16-alkyl, heteroaryl-C26-alkenyl or heteroaryl-C26-alkynyl, of which the cyclic moieties optionally may be substituted with one or more substitu- ents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR21, -NR21R22 and C1-6-alkyl, wherein R21 and R22 independently are hydrogen, C1-6-alkyl or aryl, or R21 and R22 when attached to the same nitrogen atom together with the said nitro- gen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R15 to 18 when placed in adjacent positions together may form a bridge -(CR23R24)a-O-(CR25R26)c-O-, wherein a is 0, 1 or 2, cis 1 or 2, R23, R24, R25 and R26 independently are hydrogen, C16-alkyl or fluorine, R'9 and R20 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl or C38-cyclo- alkyl-C1-6-alkyl, E is

wherein R27 and R28 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OR32, -NR32R33, C1-6-alkyl, C3-8-cycloalkyl, C4-8-cycloalkenyl or aryl, wherein the aryl group optionally may be substituted with one or more substituents selected from halogen,-CN,-CF3,-OCF3,-N02,-OR32,-NR32R33 and C16-alkyl, wherein R32 and R33 independently are hydrogen or C16-alkyl, or R32 and R33 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally con- taining one or two double bonds, R29, R30 and R31 independently are hydrogen, halogen,-CHF2,-CF3,-OCF3,-OCHF2,-OCH2CF3,-OCF2CHF2,-SCF3, -OR34, -NR34R35, -SR34, -S(O)R34, -S(O)2R34, -C(O)NR34R35, -OC(O)NR34R35, - C (O) R35,-OCH2C (O) NR34R35,-C (O) R34or-C (O) OR,

Cl-6-alkyl, C2-6-alkenyl or C2-6-alkynyl, which may optionally be substituted with one or more substituents selected from halogen,-CN,-CF3,-OCF3,-NO2,-OR34,-NR34R35 and C16-alkyl, C3-8-cycloalkyl, C4-8-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cyclo- alkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cyclo- alkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, heterocyclyl-C1-6-alkyl, heterocy- clyl-C2-6-alkenyl, heterocyclyl-C2-alkynyl, aryl, aryloxy, aroyl, aryl-C1-alkoxy, aryl- C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, hetero- aryl-C2-6-alkenyl or heteroaryl-C2-6-alkynyl, of which the cyclic moieties optionally may be substituted with one or more substitu- ents selected from halogen,-CN,-CF3,-OCF3,-NO2,-oR34,-NR34R35 and C16-alkyl, wherein R34 and R35 independently are hydrogen, C16-alkyl or aryl, or R34 and R35 when attached to the same nitrogen atom together with the said nitro- gen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R29, R30 and R31 when attached to the same ring carbon atom or different ring carbon atoms together may form a radical -O-(CH2)t-CR36R37-(CH2)l-O-, -(CH2)t-OR36R37-(CH2)l- or -S-(CH2)t-CR36R37-(CH2)l-S-, wherein t and I independently are 0,1, 2,3, 4 or 5, R36 and R3'independently are hydrogen or C16-alkyl, as well as any optical or geometric isomer or tautomeric form thereof including mix- tures of these or a pharmaceutical acceptable salt thereof.

The compounds of the present invention may have one or more asymmetric centres and it is intended that any optical isomers, as separated, pure or partially

purified optical isomers or racemic mixtures thereof are included within the scope of the invention.

Furthermore, when a double bond or a fully or partially saturated ring system is present in the molecule geometric isomers may be formed. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are included within the scope of the invention. Likewise, molecules having a bond with restricted rotation may form geometric isomers. These are also intended to be included within the scope of the present invention.

Furthermore, some of the compounds of the present invention may exist in different tautomeric forms and it is intended that any tautomeric forms that the com- pounds are able to form are included within the scope of the present invention.

The acid addition salts may be obtained as the direct products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent

containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.

The compounds of the present invention may form solvates with standard low molecular weight solvents using methods well known to the person skilled in the art. Such solvates are also contemplated as being within the scope of the present invention.

The invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before be- coming pharmacologically active substances. In general, such prodrugs will be func- tional derivatives of the compounds of the general formula (I), which are readily con- vertible in vivo into the required compound of the formula (I). Conventional proce- dures for the selection and preparation of suitable prodrug derivatives are described, for example, in"Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

The invention also encompasses active metabolites of the present com- pounds.

The compounds according to the present invention act to antagonize the ac- tion of glucagon and are accordingly useful for the treatment and/or prevention of disorders and diseases in which such an antagonism is beneficial.

Furthermore, they may be applicable as diagnostic agents for identifying pa- tients having a defect in the glucagon receptor, as a therapy to increase gastric acid se- cretions and to reverse intestinal hypomobility due to glucagon administration.

They may also be useful as tool or reference molecules in labelled form in binding assays to identify new glucagon antagonists.

Accordingly, in a further aspect the invention relates to a compound accord- ing to the invention for use as a medicament.

The invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound according to the invention together with one or more pharmaceutically acceptable carriers or excipients.

The pharmaceutical composition is preferably in unit dosage form, compris- ing from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and especially preferred from about 0.5 mg to about 200 mg of the compound according to the invention.

Furthermore, the invention relates to the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment and/or prevention of a disorder or disease, wherein a glucagon antagonistic action is beneficial.

The invention also relates to a method for the treatment and/or prevention of disorders or diseases, wherein a glucagon antagonistic action is beneficial the method comprising administering to a subject in need thereof an effective amount of a compound according to the invention.

In a preferred embodiment of the invention the present compounds are used for the preparation of a medicament for the treatment and/or prevention of any gluca- gon-mediated conditions and diseases.

In a preferred embodiment of the invention the present compounds are used for the preparation of a medicament for the treatment and/or prevention of hypergly- cemia.

In yet a preferred embodiment of the invention the present compounds are used for the preparation of a medicament for lowering blood glucose in a mammal.

The present compounds are effective in lowering the blood glucose, both in the fast- ing and the postprandial stage.

In another preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of IGT.

In still another preferred embodiment of the invention the present com- pounds are used for the preparation of a pharmaceutical composition for the treat- ment and/or prevention of Type 2 diabetes.

In yet another preferred embodiment of the invention the present com- pounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to Type 2 diabetes.

In yet another preferred embodiment of the invention the present com- pounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from non-insulin requiring Type 2 diabetes to insulin requiring Type 2 diabetes.

In a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of Type 1 diabetes. Such treatment and/or prevention is normally accom- panied by insulin therapy.

In a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of obesity.

In yet a further preferred embodiment of the invention the present com- pounds are used for the preparation of a pharmaceutical composition for the treat- ment and/or prevention of disorders of the lipid metabolism.

In still a further preferred embodiment of the invention the present com- pounds are used for the preparation of a pharmaceutical composition for the treat- ment and/or prevention of an appetite regulation or energy expenditure disorder.

In a further aspect of the invention, treatment of a patient with the present compounds is combined with diet and/or exercise.

In still a further aspect of the invention the present compounds are adminis- tered in combination with one or more further active substances in any suitable ratios.

Such further active substances may eg be selected from antiobesity agents, antidia- betics, antihypertensive agents, agents for the treatment of complications resulting from or associated with diabetes and agents for the treatment of complications and disorders resulting from or associated with obesity.

Thus, in a further aspect of the invention the present compounds may be administered in combination with one or more antiobesity agents or appetite regulat- ing agents.

In one embodiment, the present compounds are administered in combina- tion with insulin or an insulin analogue or derivative, such as N8B29-tetradecanoyl des (B30) human insulin, AspB28 human insulin, LysB2B ProB29 human insulin, Lantus, or a mix-preparation comprising one or more of these.

In a further embodiment of the invention the present compounds are admin- istered in combination with a sulphonylurea eg tolbutamide, chlorpropamide, to- lazamide, glibenclamide, glipizide, glimepiride, glicazide or glyburide.

In another embodiment of the invention the present compounds are adminis- tered in combination with a biguanide eg metformin.

In yet another embodiment of the invention the present compounds are ad- ministered in combination with a meglitinide eg repaglinide or nateglinide.

In still another embodiment of the invention the present compounds are ad- ministered in combination with a thiazolidinedione insulin sensitizer eg troglitazone, ciglitazone, pioglitazone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS- 011/CI-1037 or T 174 or the compounds disclosed in WO 97/41097, WO 97/41119, WO 97/41120, WO 00/41121 and WO 98/45292 (Dr. Reddy's Research Foundation), which are incorporated herein by reference.

In a further embodiment of the invention the present compounds are admin- istered in combination with an a-glucosidase inhibitor eg voglibose, emiglitate, migli- tol or acarbose.

In another embodiment of the invention the present compounds are adminis- tered in combination with an agent acting on the ATP-dependent potassium channel of the (3-cells eg tolbutamide, glibenclamide, glipizide, glicazide, BTS-67582 or repag- linide.

In yet another embodiment of the invention the present compounds may be administered in combination with nateglinide.

In still another embodiment of the invention the present compounds are ad- ministered in combination with an antilipidemic agent eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyrox- ine.

In another aspect of the invention, the present compounds are administered in combination with more than one of the above-mentioned compounds eg in combi- nation with metformin and a sulphonylurea such as glyburide ; a sulphonylurea and acarbose; nateglinide and metformin; acarbose and metformin ; a sulphonylurea, met- formin and troglitazone ; insulin and a sulphonylurea ; insulin and metformin ; insulin, metformin and a sulphonylurea ; insulin and troglitazone ; insulin and lovastatin ; etc.

Furthermore, the present compounds may be administered in combination with one or more antihypertensive agents. Examples of antihypertensive agents are ß-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, AGE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enala- pril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and a-blockers such as doxazosin, urapidil, prazosin and terazosin. Further refer- ence can be made to Remington: The Science and Practice of Pharmacy, 19'h Edi- tion, Gennaro, Ed. , Mack Publishing Co. , Easton, PA, 1995.

It should be understood that any suitable combination of the compounds ac- cording to the invention with diet and/or exercise, one or more of the above- mentioned compounds and optionally one or more other active substances are con- sidered to be within the scope of the present invention.

PHARMACEUTICAL COMPOSITIONS The compounds of the invention may be administered alone or in combina- tion with pharma-ceutically acceptable carriers or excipients, in either single or multi- ple doses. The pharmaceu-tical compositions according to the invention may be for- mulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed. , Mack Publishing Co. , Easton, PA, 1995.

The pharmaceutical compositions may be specifically formulated for admini- stration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (in- cluding buccal and sublingual), transdermal, intracistemal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the pre- ferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.

Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art.

Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emul- sions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as be- ing within the scope of the present invention.

A typical oral dosage is in the range of from about 0. 001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day ad- ministered in one or more dosages such as 1 to 3 dosages. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition

treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.

The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral admini- stration one or more times per day such as 1 to 3 times per day may contain from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more pre- ferred from about 0.5 mg to about 200 mg.

For parenteral routes such as intravenous, intrathecal, intramuscular and simi- lar administration, typically doses are in the order of about half the dose employed for oral administration.

The compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof. One example is an acid addition salt of a compound having the utility of a free base. When a compound of the formula (I) con- tains a free base such salts are prepared in a conventional manner by treating a solu- tion or suspension of a free base of the formula (I) with a chemical equivalent of a pharmaceutical acceptable acid. Representative examples are mentioned above.

Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion.

For parenteral administration, solutions of the novel compounds of the formula (I) in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed. Such aqueous solutions should be suitably buffered if necessary and the liq- uid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solu- tions are particularly suitable for intravenous, intramuscular, subcutaneous and intrap- eritoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.

Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, poly- oxyethylene and water. Similarly, the carrier or diluent may include any sustained re- lease material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by combining the novel compounds of the formula (I) and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes

of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predeter- mined amount of the active ingredient, and which may include a suitable excipient. Fur- thermore, the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or wa- ter-in-oil liquid emulsion.

If a solid carrier is used for oral administration, the preparation may be ta- bletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usu- ally be from about 25 mg to about 1 g. if a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

If desired, the pharmaceutical composition of the invention may comprise the compound of the formula (I) in combination with further pharmacologically active substances such as those described in the foregoing.

EXAMPLES The preparation of the compounds of the present invention is described in detail using the following examples, but the chemical reactions described are dis- closed in terms of their general applicability to the preparation of the glucagon an- tagonists of the invention. Occasionally, the reaction may not be applicable as de- scribed to each compound included within the disclosed scope of the invention. The compounds for which this occurs will be readily recognised by those skilled in the art.

In these cases the reactions can be successfully performed by conventional modifi- cations known to those skilled in the art, that is, by appropriate protection of interfer- ing groups, by changing to other conventional reagents, or by routine modification of reaction conditions. Alternatively, other reactions disclosed herein or otherwise con- ventional will be applicable to the preparation of the corresponding compounds of the invention. In all preparative methods, all starting materials are known or may easily be prepared from known starting materials. All temperatures are set forth in degrees Celsius and unless otherwise indicated, all parts and percentages are by weight when referring to yields and all parts are by volume when referring to solvents and eluent.

Some of the NMR data shown in the following examples are only selected data.

The Sciex Sample control software running on a Macintosh PowerPC 7200 computer was used for the instrument control and data acquisition.

The HPLC pump was connected to four eluent reservoirs containing: A: Acetonitrile B: Water C: 0.5% TFA in water D: 0.02 M ammonium acetate The requirements for samples are that they contain approximately 500 wg/ml of the compound to be analysed in an acceptable solvent such as methanol, ethanol, acetonitrile, THF, water and mixtures thereof. (High concentrations of strongly eluting solvents will interfere with the chromatography at low acetonitrile concentrations.) The analysis was performed at room temperature by injecting 20 pl of the sample solution on the column, which was eluted with a gradient of acetonitrile in ei- ther 0.05% TFA or 0.002 M ammonium acetate. Depending on the analysis method varying elution conditions were used.

The eluate from the column was passed through a flow splitting T-connector, which passed approximately 20 p, l/min through approx. 1 m 75 g fused silica capillary to the API interface of API 100 spectrometer.

The remaining 1.48 ml/min was passed through the UV detector and to the ELS detector.

During the LC-analysis the detection data were acquired concurrently from the mass spectrometer, the UV detector and the ELS detector.

Building blocks to be used in examples 29 to 32 1 (2)- (1-methoxy-1-methylethl)-5-methvl-1 (2) H-tetrazole 5-methyltetrazole (3,5g, 42 mmol) was suspended in toluene (100 ml) and 2,2-dimethoxypropane (20 ml) was added. The suspension was heated for 1h at re- flux, whereby a clear solution was obtained. Solvent was removed by rotary evapora- tion and the residual oil was stripped twice from acetonitrile. The title product was obtained as a 1: 5 mixture of isomers.

{S)-1-(4-Bromophenyl) ethyl isocyanate The compound was prepared by the same procedure as described above for (R)-1- (4-Bromophenyl) ethyl isocyanate using (S)-1-(4-bromophenyl)ethyl amine as starting material.

The reaction mixture was concentrated in vacuo, and the residue was dissolved in water (50 ml), acidified with hydrochloric acid (4 N, 14 ml), and extracted with ethyl acetate (50 ml). The aqueous phase was extracted with ethyl acetate (50 ml). The combined organic phases were washed with water (3 x 30 ml), dried (magnesium sulphate) and concentrated in vacuo. The residue was crystallised from ethyl ace-

After 10 min the mixture was concentrated in vacuo and the residue was evaporated from toluene three times (4 ml). The residue was suspended in toluene (4 ml) and diphosgene (0.20 ml, 1.7 mmol) was added. The reaction mixture was stirred at 120 °C for 3 hours and concentrated in vacuo. The residue was evaporated from toluene three times (4 ml). The residue was dissolved in DCM (1 ml) and added to a solution of 4- [ (4-teft-butylphenylamino) methyl]-N- (5-oxo-4, 5-dihydro- [1, 2,4] oxadiazol-3-yl- methyl) benzamide hydrochloride (130 mg, 0.31 mmol) and diisopropylethylamine (44 mg, 0.34 mmol) in DCM (2 ml). The reaction mixture was stirred for 16 hours at 20 °C and concentrated in vacuo. The residue was purified by column chromatography on silica gel (33 g) using a mixture of DCM and 10% ammonia in ethanol (7: 3) to afford 54 mg of the title compound.

Step 1: Preparation of 5- (4-formylphenyl) penta-2, 4-dienoic acid To an ice cooled solution of sodium hydride (2.26 g, 67.2 mmol as a 60% mineral oil suspension) in dry THF (100 ml) was added dropwise a solution of trimethyl-4-phosphonocrotonate (10.5 g, 50.4 mmol) in dry THF (200 ml), and the so- lution was stirred under an inert atmosphere at 0 °C for 3 hours. Terephthaldialde- hyde mono diethyl acetal (7.00 g, 33.6 mmol) was dissolved in dry THF (200 ml) and slowly added to the above solution. Stirring was continued for 2 hours at 0 °C. Water (400 mi) was slowly added, and followed by ethyl acetate (500 mi) and the layers were mixed. The organic layer was collected and dried with anhydrous sodium sul- phate. Solvent was removed by rotary evaporation to leave 10.0 g of a crude orange product that was dissolved in ethanol (20 ml) and added a solution of 20% potassium hydroxide (100 ml). The mixture was stirred at room temperature for 5 hours, and then partitioned between ethyl acetate (500 mi) and water (500 ml). The organic layer was washed with water (200 ml), and the combined water phases back extracted once with ethyl acetate (300 ml). The water phase was acidified with glacial acetic acid to pH 3.5, and extracted with ethyl acetate (2 x 500 ml). The organic layer was dried with sodium sulphate, and taken to dryness to leave the title material as an or- ange powder. Yield : 6.78 g (100%).

Triethyl 4-phosphonocrotonate (145 mg; 0.65 mmol) was dissolved in dry THF (2.0 mi) and sodium hydride (50 mg; 60% oil suspension, 1.24 mmol) was added. The mixture was stirred a 0 °C for 10 minutes before introducing a solution of 1- (4-cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl)-1- (4-formylbenzyl) urea (150 mg; 0.31 mmol) in THF (2.0 ml). The solution was stirred at 0 °C for 1 hour. Water (1 mi) was added and stirring was continued for further 30 min at room temperature. Sol- vent was removed by rotary evaporation, and the residual oil was dissolved in water (5 mi). The title compound was precipitated out of solution by addition of acetic acid (1.0 ml), collected by filtration and washed with water. Yield : 150 mg.

Step 1: 1-(4-Diethoxymethylphenvl) prop-2-en-1-ol To an ice-cooled solution of terephthaldialdehyde mono-diethylacetal (9.95 ml, 50 mmol) in THF (100 ml) was added dropwise a solution of vinyl magnesium bromide in THF (55 ml, 1 M, 55 mmol) at such rate, that the internal reaction tem- perature did not exceed 10 °C. After addition, the solution was stirred at room tem- perature for 2 hours, before slow quenching with a saturated solution of aqueous ammonium chloride (100 ml). Water (100 ml) and ethyl acetate (200 ml) was added, and the two-phase system was stirred vigorously for 10 min. The organic phase was separated, washed once with saturated aqueous ammonium chloride (100 ml), dried over anhydrous sodium sulphate and then evaporated to dryness. The crude product was further purified by silica gel column chromatography using 25% ethyl acetate in heptane as eluent. Pure fractions were pooled and evaporated to dryness to give the title material as faint yellow oil. Yield : 3.60 g (31%).

The temperature was then lowered to-78 °C, and a solution of terephthaldialdehyde mono-diethylacetal (6.8 ml, 34 mmol) in THF (100 ml) was added dropwise over 10 min, while the clear dark reacton mixture changed color from dark to yellow. Tem- perature was again raised to 0 °C, and the mixture was quenched with acetic acid (4.3 ml). The mixture was stirred at room temperature for 5 hours and then parti- tioned between ethyl acetate (500 ml) and water (500 ml). The organic layer was washed once with water (500 ml), then in a row with 1 N aqueous sodium hydroxide (2 x 250 ml), 10% aqueous sodium sulfite solution (2 x 250 ml) and brine (250 ml).

The organic phase was then dried with anhydrous sodium sulfate and taken to dry- ness by rotary evaporation. The residue was suspended in 1 N aqueous HCI (100 ml) and heated to reflux for 2 hours. The clear solution thus obtained was filtered while hot, then cooled and taken to dryness. The residue was stripped twice from acetoni- trile to give pure title material as off-white crystals.

The mixture was heated to reflux for 30 min to complete imin formation, then cooled to 0 °C on an ice bath. The crystalline pure trans form was then collected by filtration, and dried overnight in vacuo. Yield : 15.3 g (78%).

Solvent was removed by rotary evaporation, and the residue was dissolved in ethyl acetate (100 ml). The organic phase was washed once with saturated aqueous so- dium hydrogen carbonate (100 ml) ; dried over anhydrous sodium sulphate and taken

to dryness by rotary evaporation to leave 1.0 g (100%) of the title material as an clear oil.

To a solution of 2-(1-methoxy-1-methylethyl)-5-methyl-2H-tetrazole (1000 mg, 6.41 mmol) in THF (5 ml) cooled to-78 °C on a dry-ice-acetone bath was added dropwise a solution of n-butyl lithium in hexanes (4.0 ml, 1.6 M, 6.4 mmol). The mix- ture was stirred at-78°C for 30 min, and at 0 °C for an additional 30 min, then re- cooled to-78 °C. 1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl)-1- (4-formyl- benzyl) urea (250 mg, 0.52 mmol, from step 2, example 12) was then added as a solid, and the mixture was maintained at-78 °C for 20 min. Reaction temperature was raised to 0°C and the mixture was stirred for 20 min before addition of acetic acid (2 ml). Upon standing, a white solid starts to precipitate, which is collected and washed with cold acetonitrile. The solid is oven dried under vacuum, to yield 582 mg (95 %).

drich) was added, leading to immediate precipitation of white crystals. The mixture was heated to reflux for 30 min to complete imine formation and then cooled to 0 °C on an ice bath. The crystalline pure trans form was then collected by filtration, and dried overnight in vacuo. Yield : 15. 3 g (78%).

Step 10: 3-[1(R)-(4-bromophenyl)ethyl]-1-(4-tert-butylcyclohexyl)-1-{
4-[1(R/S)-hydroxy-2-(2H- tetrazol-5-yl)hethyllbenzvlurea The above described resin was treated with 50% TFA in DCM for 30 min. The sol- vent was collected and removed by nitrogen air flow, to give the title material as a crystalline solid.

PHARMACOLOGICAL METHODS In the following section binding assays as well as functional assays useful for evalu- ating the efficiency of the compounds of the invention are described.

Binding of compounds to the glucagon receptor may be determined in a competition binding assay using the cloned human glucagon receptor.

Antagonism may be determined as the ability of the compounds to inhibit the amount of cAMP formed in the presence of 5 nM glucagon.

Glucagon Binding Assay (I) Receptor binding is assayed using cloned human receptor (Lok et al., Gene 140,203- 209 (1994) ). The receptor inserted in the pLJ6'expression vector using EcoRI/SSt1 restriction sites (Lok et al.) is expressed in a baby hamster kidney cell line (A3 BHK 570-25). Clones are selected in the presence of 0.5 mg/ml G-418 and are shown to be stable for more than 40 pas- sages. The Kd is shown to be 0.1 nM.

Plasma membranes are prepared by growing cells to confluence, detaching them from the surface and resuspending the cells in cold buffer (10 mM tris/HCI, pH 7.4 containing 30 mM NaCI, 1 mM dithiothreitol, 5 mg/i leupeptin (Sigma), 5 mg/i pepstatin (Sigma), 100 mg/l ba- citracin (Sigma) and 15 mg/l recombinant aprotinin (Novo Nordisk A/S) ), homogenization by two 10-s bursts using a Poltron PT 10-35 homogenizer (Kinematica), and centrifugation upon a layer of 41 w/v % sucrose at 95.000 x g for 75 min. The white band located between the two layers is diluted in buffer and centrifuged at 40.000 x g for 45 min. The precipitate containing the plasma membranes is suspended in buffer and stored at-80 °C until use.

Glucagon is iodinated according to the chloramine T method (Hunter and Greenwood, Nature 194,495 (1962) ) and purified using anion exchange chromatography (Jargensen et al., Hormone and Metab. Res. 4,223-224 (1972). The specific activity is 46011Ci/, ug on the day of iodination. Tracer is stored at-18 °C in aliquots and are used immediately after thawing.

Binding assays are carried out in triplicate in filter microtiter plates (MADV N65, Milli- pore). The buffer used in this assay is 50 mM HEPES, 5 mM EGTA, 5 mM MgCI2, 0.005% tween 20, pH 7.4. Glucagon is dissolved in 0.05 M HCI, added an equal amount (w/w) of human serum albim and freeze-dried. On the day of use, it is dissolved in water and diluted in buffer to the desired concentrations.

Test compounds are dissolved and diluted in DMSO. 140 pI buffer, 25111 glucagon or buffer, and 10 pl DMSO or test compound are added to each well. Tracer (50.000 cpm) is di- luted in buffer and 25 gl are added to each well. 1-4 gag freshly thawed plasma membrane pro- tein diluted in buffer is then added in aliquots of 25 ul to each well. Plates are incubated at 30 °C

for 2 hours. Non-specific binding is determined with 10 M of glucagon. Bound tracer and un- bound tracer are then separated by vacuum filtration (Millipore vacuum manifold). The plates are washed with 2 x 100) J buffer we)). The plates are air dried for a couple of hours, where- upon the filters are separated from the plates using a Millipore Puncher. The filters are counted in a gamma counter.

The total assay volume is 140 il. The plates are incubated for 2 hours at 37 °C with continuous shaking. Reaction is terminated by addition of 25 ; ni 0. 5 N HCI. cAMP is measured by the use of a scintillation proximity kit (Amersham).

Glucagon Binding Assay (II) BHK (baby hamster kidney cell line) cells are transfected with the human glucagon receptor and a membrane preparation of the cells is prepared. Wheat Germ Agglutinin derivatized SPA beads containing a scintillant (WGA beads) (Amersham) bound the membranes. 1251-glucagon bound to human glucagon receptor in the membranes and excited the scintillant in the WGA beads to light emission. Glucagon or samples binding to the receptor competed with 125I-glucagon.

All steps in the membrane preparation are kept on ice or performed at 4 °C. BHK cells are harvested and centrifuged. The pellet is resuspended in homogenisation buffer (25 mM HEPES, pH = 7.4, 2.5 mM CaC12, 1-0 MM MgC12, 250 mg/I bacitracin, 0.1 mM Pefabloc), homogenised 2 x 10 sec using Poltron 10-35 homogenizer (Kinematica) and added the same amount of homogenisation buffer as used for resuspension. After centrifugation (15 min at 2000 x g) the supernatant is transferred to cold centrifuge tubes and centrifuged for 45